This invention relates to endothelin antagonists useful, inter alia, for treatment of hypertension.
Compounds of the formula 
and pharmaceutically acceptable salts thereof are endothelin receptor antagonists useful, inter alia, as antihypertensive agents. Throughout this specification, the above symbols are defined as follows:
one of X and Y is N and the other is O;
R1, R2 and R3 are each independently
(a) hydrogen, except that R1 is other than hydrogen;
(b) alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, aryloxy, aralkyl or aralkoxy, any of which may be substituted with Z1, Z2 and Z3;
(c) halo;
(d) hydroxyl;
(e) cyano;
(f) nitro;
(g) xe2x80x94C(O)H or xe2x80x94C(O)R6;
(h) xe2x80x94CO2H or xe2x80x94CO2R6;
(i) xe2x80x94SH, xe2x80x94S(O)nR6, xe2x80x94S(O)mxe2x80x94OH, xe2x80x94S(O)mxe2x80x94OR6, xe2x80x94Oxe2x80x94S(O)mxe2x80x94R6, xe2x80x94Oxe2x80x94S(O)mOH or xe2x80x94Oxe2x80x94S(O)mxe2x80x94OR6;
(j) xe2x80x94Z4xe2x80x94NR7R8; or
(k) xe2x80x94Z4xe2x80x94N(R11)xe2x80x94Z5xe2x80x94NR9R10;
R4 and R5 are each independently
(a) hydrogen;
(b) alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, aryloxy, aralkyl or aralkoxy, any of which may be substituted with Z1, Z2 and Z3;
(c) halo;
(d) hydroxyl;
(e) cyano;
(f) nitro;
(g) xe2x80x94C(O)H or xe2x80x94C(O)R6;
(h) xe2x80x94CO2H or xe2x80x94CO2R6;
(i) xe2x80x94SH, xe2x80x94S(O)nR6, xe2x80x94S(O)mxe2x80x94OH, xe2x80x94S(O)mxe2x80x94OR6; xe2x80x94Oxe2x80x94S(O)mxe2x80x94R6, xe2x80x94Oxe2x80x94S(O)mOH or xe2x80x94Oxe2x80x94S(O)mxe2x80x94OR6;
(j) xe2x80x94Z4xe2x80x94NR7R8;
(k) xe2x80x94Z4xe2x80x94N(R11)xe2x80x94Z5xe2x80x94NR9R10; or
(l) R4 and R5 together are alkylene or alkenylene (either of which may be substituted with Z1, Z2 and Z3), completing a 4- to 8-membered saturated, unsaturated or aromatic ring together with the carbon atoms to which they are attached;
R6 is alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl or aralkyl, any of which may be substituted with Z1, Z2 and Z3;
R7 is
(a) hydrogen;
(b) alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl or aralkyl, any of which may be substituted with Z1, Z2 and Z3;
(c) cyano;
(d) hydroxyl;
(e) xe2x80x94C(O)H or xe2x80x94C(O)R6;
(f) xe2x80x94CO2R6;
(g) xe2x80x94SH, xe2x80x94S(O)nR6, xe2x80x94S(O)mxe2x80x94OH, xe2x80x94S(O)mxe2x80x94OR6, xe2x80x94Oxe2x80x94S(O)mxe2x80x94R6, xe2x80x94Oxe2x80x94S(O)mOH or xe2x80x94Oxe2x80x94S(O)mxe2x80x94OR6, except when Z4 is xe2x80x94S(O)nxe2x80x94;
R8 is
(a) hydrogen;
(b) xe2x80x94C(O)H or xe2x80x94C(O)R6, except when Z4 is xe2x80x94C(O)xe2x80x94 and R7 is xe2x80x94C(O)H, xe2x80x94C(O)R6 or xe2x80x94CO2R6;
(c) alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl or aralkyl, any of which may be substituted with Z1, Z2 and Z3; or
R7 and R8 together are alkylene or alkenylene (either of which may be substituted with Z1, Z2 and Z3), completing a 3- to 8-membered saturated, unsaturated or aromatic ring together with the nitrogen atom to which they are attached;
R9 is
(a) hydrogen;
(b) hydroxyl;
(c) xe2x80x94C(O)H or xe2x80x94C(O)R6;
(d) xe2x80x94CO2R6;
(e) xe2x80x94SH, xe2x80x94S(O)nR6, xe2x80x94S(O)mxe2x80x94OH, xe2x80x94S(O)mxe2x80x94OR6, xe2x80x94Oxe2x80x94S(O)mR6, xe2x80x94Oxe2x80x94S(O)mOH or xe2x80x94Oxe2x80x94S(O)mxe2x80x94OR6;
(f) alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl or aralkyl, any of which may be substituted with Z1, Z2 and Z3;
R10 is
(a) hydrogen;
(b) xe2x80x94C(O)H or xe2x80x94C(O)R6, except when Z5 is xe2x80x94C(O)xe2x80x94 and R9 is xe2x80x94C(O)H, xe2x80x94C(O)R6 or xe2x80x94CO2R6; or
(c) alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl or aralkyl, any of which may be substituted with Z1, Z2 and Z3;
R11 is
(a) hydrogen;
(b) hydroxyl;
(c) xe2x80x94C(O)H, xe2x80x94C(O)R6 or CO2R6; or
(d) alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl or aralkyl, any of which may be substituted with Z1, Z2 and Z3;
or any two of R9, R10 and R11 together are alkylene or alkenylene (either of which may be substituted with Z1, Z2 and Z3), completing a 3- to 8-membered saturated, unsaturated or aromatic ring together with the atoms to which they are attached;
Z1, Z2 and Z3 are each independently
(a) hydrogen;
(b) halo;
(c) hydroxy;
(d) alkyl;
(e) alkenyl;
(f) aralkyl;
(g) alkoxy;
(h) aryloxy;
(i) aralkoxy;
(j) xe2x80x94SH, xe2x80x94S(O)nZ6, xe2x80x94S(O)mxe2x80x94OH, xe2x80x94S(O)mxe2x80x94OZ6, xe2x80x94Oxe2x80x94S(O)mxe2x80x94Z6, xe2x80x94Oxe2x80x94S(O)mOH or xe2x80x94Oxe2x80x94S(O)mxe2x80x94OZ6;
(k) oxo;
(l) nitro;
(m) cyano;
(n) xe2x80x94C(O)H or xe2x80x94C(O)Z6;
(o) xe2x80x94CO2H or xe2x80x94CO2Z6;
(p) xe2x80x94Z4xe2x80x94NZ7Z8;
(q) xe2x80x94Z4xe2x80x94N(Z11)xe2x80x94Z5xe2x80x94Z6; or
(r) xe2x80x94Z4xe2x80x94N(Z11)xe2x80x94Z5xe2x80x94NZ7Z8;
Z4 and Z5 are each independently
(a) a single bond;
(b) xe2x80x94Z9xe2x80x94S(O)nxe2x80x94Z10xe2x80x94;
(c) xe2x80x94Z9xe2x80x94C(O)xe2x80x94Z10xe2x80x94;
(d) xe2x80x94Z9xe2x80x94C(S)xe2x80x94Z10xe2x80x94;
(e) xe2x80x94Z9xe2x80x94Oxe2x80x94Z10xe2x80x94;
(f) xe2x80x94Z9xe2x80x94Sxe2x80x94Z10xe2x80x94; or
(g) xe2x80x94Z9xe2x80x94Oxe2x80x94C(O)xe2x80x94Z10xe2x80x94;
Z6, Z7 and Z8 are each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl or aralkyl, or Z7 and Z8 together are alkylene or alkenylene, completing a 3- to 8-membered saturated, unsaturated or aromatic ring together with the nitrogen atom to which they are attached;
Z9 and Z10 are each independently a single bond, alkylene, alkenylene or alkynylene;
Z11 is
(a) hydrogen;
(b) hydroxyl;
(c) xe2x80x94C(O)H, xe2x80x94C(O)Z6 or xe2x80x94CO2Z6;
(d) alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl or aralkyl;
or any two of Z7, Z8 and Z11 together are alkylene or alkenylene, completing a 3- to 8-membered saturated, unsaturated or aromatic ring together with the atoms to which they are attached;
m is 1 or 2; and
n is 0, 1 or 2.
For coumpound I, it is preferred that:
R1 is phenyl or phenoxy, optionally substituted with one or more alkyl, alkoxy, xe2x80x94NZ7Z8, halo and hydroxy;
R2 and R3 are each independently hydrogen, alkyl or xe2x80x94NR7R8;
R4 and R5 are alkyl; and
R7, R8, Z7 and Z8 are each independently hydrogen, alkyl or xe2x80x94C(O)alkyl.
Most preferred compounds are those wherein:
R1 is phenyl or phenoxy, optionally substituted with alkyl, alkoxy, amino, alkylamino, dialkylamino, alkanoylamino or hydroxy;
R2 and R3 are each independently hydrogen, alkyl of 1 to 4 carbon atoms, amino, alkylamino, dialkylamino or alkanoylamino; and
R4 and R5 are alkyl of 1 to 4 carbon atoms, especially methyl.
Listed below are definitions of terms used in this specification. These definitions apply to the terms as used throughout this specification, individually or as part of another group, unless otherwise limited in specific instances.
The terms xe2x80x9calkylxe2x80x9d and xe2x80x9calkoxyxe2x80x9d refer to straight or branched chain hydrocarbon groups having 1 to 10 carbon atoms. The terms xe2x80x9clower alkylxe2x80x9d and xe2x80x9clower alkoxyxe2x80x9d refer to groups of 1 to 4 carbon atoms, which are preferred.
The term xe2x80x9carylxe2x80x9d or xe2x80x9car-xe2x80x9d refers to phenyl, naphthyl and biphenyl.
The term xe2x80x9calkenylxe2x80x9d refers to straight or branched chain hydrocarbon groups of 2 to 10 carbon atoms having at least one double bond. Groups of two to four carbon atoms are preferred.
The term xe2x80x9calkynylxe2x80x9d refers to straight or branched chain groups of 2 to 10 carbon atoms having at least one triple bond. Groups of two to four carbon atoms are preferred.
The term xe2x80x9calkylenexe2x80x9d refers to a straight chain bridge of 1 to 5 carbon atoms connected by single bonds (e.g., xe2x80x94(CH2)xxe2x80x94 wherein x is 1 to 5), which may be substituted with 1 to 3 lower alkyl groups.
The term xe2x80x9calkenylenexe2x80x9d refers to a straight chain bridge of 2 to 5 carbon atoms having one or two double bonds that is connected by single bonds and may be substituted with 1 to 3 lower alkyl groups. Exemplary alkenylene groups are xe2x80x94CHxe2x95x90CHxe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94CH2xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94CH2xe2x80x94CHxe2x95x90CHxe2x80x94CH2xe2x80x94, xe2x80x94C(CH3)2CHxe2x95x90CHxe2x80x94 and xe2x80x94CH(C2H5)xe2x80x94CHxe2x95x90CH.
The term xe2x80x9calkynylenexe2x80x9d refers to a straight chain bridge of 2 to 5 carbon atoms that has a triple bond therein, is connected by singe bonds, and may be substituted with 1 to 3 lower alkyl groups. Exemplary alkynylene groups are xe2x80x94Cxe2x89xa1Cxe2x80x94, xe2x80x94CH2xe2x80x94Cxe2x89xa1Cxe2x80x94, xe2x80x94CH(CH3)xe2x80x94Cxe2x89xa1Cxe2x80x94 and xe2x80x94Cxe2x89xa1Cxe2x80x94CH(C2H5)CH2xe2x80x94.
The term xe2x80x9calkanoylxe2x80x9d refers to groups of the formula xe2x80x94C(O)alkyl.
The terms xe2x80x9ccycloalkylxe2x80x9d and xe2x80x9ccycloalkenylxe2x80x9d refer to cyclic hydrocarbon groups of 3 to 8 carbon atoms.
The terms xe2x80x9chalogenxe2x80x9d and xe2x80x9chaloxe2x80x9d refer to fluorine, chlorine, bromine and iodine.
The compounds of formula I form salts which are also within the scope of this invention. Pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salts are preferred, although other salts are also useful, e.g, in isolating or purifying the compounds of this invention.
The compounds of formula I may form salts with alkali metals such as sodium, potassium and lithium, with alkaline earth metals such as calcium and magnesium, with organic bases such as dicyclohexylamine, benzathine, N-methyl-D-glucamide and hydrabamine, and with amino acids such as arginine, lysine and the like. Such salts may be obtained by reacting compound I with the desired ion in a medium in which the salt precipitates or in an aqueous medium followed by lyophilization.
When the R1 to R5 substituents comprise a basic moiety, such as amino or substituted amino, compound I may form salts with a variety of organic and inorganic acids. Such salts include those formed with hydrochloric acid, hydrogen bromide, methanesulfonic acid, sulfuric acid, acetic acid, maleic acid, benzenesulfonate, toluenesulfonate, and various other sulfonates, nitrates, phosphates, borates, acetates, tartrates, maleates, citrates, succinates, benzoates, ascorbates, salicylates and the like. Such salts may be formed by reacting compound I in an equivalent amount of the acid in a medium in which the salt precipitates or in an aqueous medium followed by lyophilization.
In addition, when the R1 to R5 substituents comprise a basic moiety such as amino, zwitterions (xe2x80x9cinner saltsxe2x80x9d) may be formed.
Certain of the R1 to R5 substituents of compound I may contain asymmetric carbon atoms. Such compounds of formula I may exist, therefore, in enantiomeric and diastereomeric forms and in racemic mixtures thereof. All are within the scope of this invention. When R1 is aryl, compound I may exist as enantiomers even in the absence of asymmetric carbons. All such enantiomers are also within the scope of this invention. When R1 is aryl and additionally there are asymmetric carbons present, compounds of formula I may exist in diastereomeric forms and in racemic mixtures thereof. All these are within the scope of the invention as well.
The compounds of formula I are antagonists of ET-1, ET-2 and/or ET-3 and are useful in treatment of all endothelin-dependent disorders. They are thus useful as antihypertensive agents. By the administration of a composition having one (or a combination) of the compounds of this invention, the blood pressure of a hypertensive mammalian (e.g., human) host is reduced.
The compounds of the present invention are also useful in the treatment of disorders related to renal, glomerular and mesangial cell function, including chronic renal failure, glomerular injury, renal damage secondary to old age, nephrosclerosis (especially hypertensive nephroscierosis), nephrotoxicity (including nephrotoxicity related to imaging and contrast agents), and the like. The compounds of this invention may also be useful in the treatment of disorders related to paracrine and endocrine function.
The compounds of the present invention are also useful in the treatment of endotoxemia or endotoxin shock.
The compounds of the present invention are also useful as anti-ischemic agents for the treatment of, for example, heart, renal and cerebral ischemia, coronary and cerebral vasospasm, and the like.
In addition, the compounds of this invention may also be useful as anti-arrhythmic agents; anti-anginal agents; anti-fibrillatory agents; anti-asthmatic agents; anti-atherosclerotic agents; additives to cardioplegic solutions for cardiopulmonary bypasses; adjuncts to thrombolytic therapy; and anti-diarrheal agents. The compounds of this invention may be useful in therapy for myocardial infarction; therapy for peripheral vascular disease (e.g., Raynaud""s disease); treatment of cardiac hypertrophy (e.g., hypertrophic cardiomyopathy); treatment of pulmonary hypertension; treatment of central nervous system vascular disorders, such as stroke, migraine and subarachnoid hemorrhage; treatment of central nervous system behavioral disorders; treatment of gastrointestinal diseases such as ulcerative colitis and Crohn""s disease; regulation of cell growth; treatment of benign prostatic hypertrophy; restenosis following angioplasty or following any procedures including transplantation; therapy for congestive heart failure including inhibition of fibrosis; inhibition of left ventricular dilatation, remodeling and dysfunction; and treatment of hepatoxicity and sudden death.
The compounds of this invention can also be formulated in combination with endothelin converting enzyme (ECE) inhibitors, such as phosphoramidon; platelet activating factor (PAF) antagonists; angiotensin II (AII) receptor antagonists; renin inhibitors; angiotensin converting enzyme (ACE) inhibitors such as captopril, zofenopril, fosinopril, ceranapril, alacepril, enalapril, delapril, pentopril, quinapril, ramipril, lisinopril and salts of such compounds; neutral endopeptidase (NEP) inhibitors; HMG CoA reductase inhibitors such as pravastatin and mevacor; squalene synthetase inhibitors; bile acid sequestrants such as questran; calcium channel blockers; potassium channel activators; beta-adrenergic agents; antiarrhythmic agents; diuretics, such as chlorothiazide, hydrochlorothiazide, flumethiazide, hydroflumethiazide, bendroflumethiazide, methylchlorothiazide, trichloromethiazide, polythiazide or benzothiazide as well as ethacrynic acid, tricrynafen, chlorthalidone, furosemide, musolimine, bumetanide, triamterene, amiloride and spironolactone and saltsof such compounds; and thrombolytic agents such as tissue plasminogen activator (tPA), recombinant tPA, streptokinase, urokinase, prourokinase and anisoylated plasminogen streptokinase activator complex (APSAC). If formulated as a fixed dose, such combination products employ the compounds of this invention within the dosage range described below and the other pharmaceutically active agent within its approved dosage range. The compounds of this invention may also be formulated with, or useful in conjunction with, antifungal and immunosuppressive agents such as amphotericin B, cyclosporins and the like to counteract the glomenular contraction and nephrotoxicity secondary to such compounds. The compounds of this invention may also be used in conjunction with hemodialysis.
The compounds of the invention can be administered orally or parenterally to various mammalian species known to be subject to such maladies, e.g., humans, in an effective amount within the dosage range of about 0.1 to about 100 mg/kg, preferably about 0.2 to about 50 mg/kg and more preferably about 0.5 to about 25 mg/kg (or from about 1 to about 2500 mg, preferably from about 5 to about 2000 mg) in single or 2 to 4 divided daily doses.
The active substance can be utilized in a composition such as tablet, capsule, solution or suspension containing about 5 to about 500 mg per unit dosage of a compound or mixture of compounds of formula I or in topical form for wound healing (0.01 to 5% by weight compound of formula I, 1 to 5 treatments per day). They may be compounded in a conventional manner with a physiologically acceptable vehicle or carrier, excipient, binder, preservative, stabilizer, flavor, etc., or with a topical carrier such as Plastibase (mineral oil gelled with polyethylene) as called for by accepted pharmaceutical practice.
The compounds of the invention may also be administered topically to treat peripheral vascular diseases and as such may be formulated as a cream or ointment.
The compounds of formula I can also be formulated in compositions such as sterile solutions or suspensions for parenteral administration. About 0.1 to 500 milligrams of a compound of formula I is compounded with a physiologically acceptable vehicle, carrier, excipient, binder, preservative, stabilizer, etc., in a unit dosage form as called for by accepted pharmaceutical practice. The amount of active substance in these compositions or preparations is such that a suitable dosage in the range indicated is obtained.
The compounds of the present invention may be prepared as follows.
An amine 
is treated with an acid (e.g., hydrochloric acid) and sodium nitrite in a solvent (e.g., water, acetic acid) at about xe2x88x9220 to 0xc2x0 C., followed by sulfur dioxide, and a copper (I) salt (e.g., copper (I) chloride) in a solvent (e.g., acetic acid) at about 5 to 30xc2x0 C. to form a sulfonyl halide 
When R1 is halogen and one of R2 or R3 is alkoxy or aralkoxy, the sulfonyl halide of the formula III can also be prepared by alkylating, in the presence of a base, the hydroxy group of a hydroxy benzene sulfonate, halogenating the ring, and then treating with a halogenating agent (e.g, PCl5). Sulfonyl halide III is then coupled with an isoxazolamine 
in an anhydrous organic solvent (e.g., pyridine) to form compound I.
Compound I wherein R1, R2 or R3 is aryl may be prepared by metal (e.g., palladium (0)) catalyzed coupling of the associated halo compound I (wherein R1, R2 or R3 is halogen) with aryl metalloids (i.e., aryl derivatives of tin, silicon, boron and the like, such as phenylboronic acid). See, for example, the procedures of Example 4. The phenylboronic acid may be prepared by treating an aryl halide with n-butyllithium or magnesium turnings in tetrahydrofuran, adding trimethylborate and finally adding aqueous hydrochloric acid. Alternatively, a phenylboronic acid may be prepared by adding a phenyl magnesium bromide to a solution of trimethyl borate and quenching with aqueous hydrochloric acid. Depending on the desired result, certain phenylboronic acids may be prepared by mixing an aryldihalide with palladium (0) and adding a grignard reagent to prepare a desired aryl halide before treating the aryl halide as described above.
Also depending on the desired result, certain phenylboronic acids may be prepared by ortho lithiation of a substituted benzene. Treatment of the substituted benzene with, for example, n-butyl lithium removes an ortho proton. Subsequent treatment with B(OCH3)3 and HCl results in an ortho-substituted phenylboronic acid. When the substituted benzene is an alkyl substituted benzene, it can be prepared, for example, by metal (e.g., palladium (0)) catalyzed coupling of a halobenzene with an alkylborane.
Certain compounds of the formula I wherein R1, R2 or R3 is aryl substituted with alkyl or cycloalkylalkyl can be similarly prepared with alkyl- or cycloalkylalkyl-phenylboronic acids. The alkyl- or cycloalkylalkyl-phenylboronic acids are prepared from the corresponding alkyl- or cycloalkylalkyl-substituted bromobenzene. These substituted bromobenzenes, in turn, can be prepared by treating substituted bromobenzaldehydes with a grignard reagent followed by elimination and hydrogenation, or with a Wittig reagent followed by hydrogenation.
There are several other alternatives for preparing a compound of the formula I wherein specifically R1 is aryl. For example, a compound of the formula I may be prepared by metal (e.g., palladium (0)) catalyzed coupling of a halobenzenesulfonamide with a phenylboronic acid. The resulting biphenyl sulfonamide is reacted with a haloisoxazole and a base (e.g., Cs2CO3).
Alternatively, a halobenzene sulfonyl chloride may be reacted with a pyrrole. The product is coupled, using a metal (e.g., palladium(0)) catalyst, with a substituted phenylboronic acid, treated with a base (e.g., NaOH) and then PCl5, and finally treated with an isoxazolamine of the formula IV.
Certain compounds of formula I in which one or more of R1 to R3 is alkylphenyl may be prepared by halogenation of the alkyl group of the appropriate alkyl phenyl group and displacement of the halogen with, for example, a cuprate reagent.
Compounds of the formula I may also be prepared by treating a halobenzene, substituted in the meta position, with ClSO3H. The resulting substituted halobenzene sulfonyl chloride is then treated as described above.
For compounds wherein any of R1 to R5 comprise reactive functionalities, the reactants may be treated with protecting agents prior to coupling. The amine portion of the sulfonamide core may also need to be protected when different R1, R2 and R3 groups are added. Suitable protecting agents and procedures for use thereof are generally known in the art. Exemplary protecting groups are benzyl, halocarbobenzyloxy, tosyl, methyl and the like for hydroxyl; and carbobenzyloxy, halocarbobenzyloxy, t-butoxy carbonyl, acetyl, benzoyl, methoxyethoxymethyl and the like for amino. The sulfonamide nitrogen may be protected with methoxyethoxymethyl, trimethylsilylethoxymethyl, t-butyl and the like. Protecting groups may be removed from the resulting protected analogues of compound I by treatment with one or more deprotecting agents. Suitable deprotecting agents and procedures for use thereof are generally known in the art.
To form compound I wherein one or more of R1 to R3 is xe2x80x94NR7R8, or R1 is phenyl-NR7R8, and R7 and/or R8 is xe2x80x94C(O)R6, the associated nonacyl sulfonic acid 
is treated with water and an alkali metal hydroxide (e.g., sodium hydroxide) to form a sulfonic acid salt 
wherein M+ a lithium, sodium or potassium ion. Salt VI is treated with an acylating agent (e.g., acetic anhydride) at about 90 to 110xc2x0 C. in either the acylating agent as solvent or in an anhydrous organic solvent (e.g., pyridine) to form the associated acylamine of formula VI, wherein one or more of R1, R2 and R3 is xe2x80x94NR 7R8, or R1 is phenyl-NR7R8, and at least one of R7 and R8 is xe2x80x94C(O)R6. Acylamine VI is then treated with a halosulfonic acid solution (e.g., chlorosulfonic acid) or with another halogenating agent (e.g., phosphorus pentachloride, thionyl chloride) at about 0xc2x0 C. to 80xc2x0 C. to form an acyl-sulfonyl halide III, which is coupled with isoxazolamine IV as described above to form compound I wherein at least one of R1, R2 and R3 is xe2x80x94NR7R8, or R1 is phenyl-NR7R8, and at least one of R7 and R8 is xe2x80x94C(O)R6.
To form a compound of formula I wherein one or more of R1 to R3 is an aldehyde or acid, or R1 is phenyl substituted with an aldehyde or acid, the corresponding hydroxyalkyl substituted benzene is oxidized.
To form a compound of formula I wherein one or more of R1 to R3 is alkoxy, the associated sulfonic acid V wherein one or more of R1 to R3 is hydroxy may be treated with an alkylating agent (e.g., dimethylsulfate) and an alkali metal hydroxide (e.g., sodium hydroxide) in an aqueous/organic solvent mixture (e.g., water/ethanol). The resulting alkoxy sulfonic acid salt VI may be used as described above to form coumpound I.
Certain compounds of formula I in which one or more of R1 to R3 is aryloxy may be prepared by displacement of the corresponding arylhalide with a metal salt of a phenol.
Monoamines of formula I (for example having xe2x80x94NR7R8 wherein one of R7 and R8 is hydrogen) are prepared from the associated free amine (for example wherein R7 and R8 are both hydrogen). The free amine is treated with (1) a ketone or aldehyde (e.g., acetone), (2) a reducing agent (e.g., sodium cyanoborohydride) or hydrogen gas (H2) and a catalyst (e.g., palladium on carbon), and (3) an acid (e.g., acetic acid, hydrochloric acid) in an organic solvent (e.g., methanol) to form the associated monoamine coumpound I. Diamines of formula I, of course, may be similarly prepared. Additionally, the monoamines may be acylated or treated with isocyanates to form ureas.
Monoamines of formula I (for example having xe2x80x94NR7R8 wherein one of R7 and R8 is hydrogen) may also be prepared from the associated acylamine by treatment with a reducing agent, for example, borane.